MicroRNA-146a gene transfer ameliorates senescence and senescence-associated secretory phenotypes in tendinopathic tenocytes.

OBJECTIVE: Tendinopathy is influenced by multiple factors, including chronic inflammation and aging. Senescent cells exhibit characteristics such as the secretion of matrix-degrading enzymes and pro-inflammatory cytokines, collectively known as senescence-associated secretory phenotypes (SASPs). Many of these SASP cytokines and enzymes are implicated in the pathogenesis of tendinopathy. MicroRNA-146a (miR-146a) blocks senescence by targeting interleukin-1ß (IL-1ß) receptor-associated kinase 4 (IRAK-4) and TNF receptor-associated factor 6 (TRAF6), thus inhibiting NF-κB activity. The aims of this study were to (1) investigate miR-146a expression in tendinopathic tendons and (2) evaluate the role of miR-146a in countering senescence and SASPs in tendinopathic tenocytes. METHODS: MiR-146a expression was assessed in human long head biceps (LHB) and rat tendinopathic tendons by in situ hybridization. MiR-146a over-expression in rat primary tendinopathic tenocytes was achieved by lentiviral vector-mediated precursor miR-146a transfer (LVmiR-146a). Expression of various senescence-related markers was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunoblotting and immunofluorescence. MiR-146a expression showed a negative correlation with the severity of tendinopathy in human and rat tendinopathic tendons (p<0.001). RESULTS: Tendinopathic tenocyte transfectants overexpressing miR-146a exhibited downregulation of various senescence and SASP markers, as well as the target molecules IRAK-4 and TRAF6, and the inflammatory mediator phospho-NF-κB. Additionally, these cells showed enhanced nuclear staining of high mobility group box 1 (HMGB1) compared to LVmiR-scramble-transduced controls in response to IL-1ß stimulation. CONCLUSIONS: We demonstrate that miR-146a expression is negatively correlated with the progression of tendinopathy. Moreover, its overexpression protects tendinopathic tenocytes from SASPs and senescence through the IRAK-4/TRAF6/NF-kB pathway.

Daily supplement of sesame oil prevents postmenopausal osteoporosis via maintaining serum estrogen and aromatase levels in rats.

Estrogen deficiency is one of the main causes of postmenopausal osteoporosis in elderly women. Hormone replacement therapy has been employed to manage postmenopausal osteoporosis; however, it has raised concerns related to heart attacks and breast cancer. Sesame oil has been reported to affect sex hormone status. The aim of the present study is to evaluate the effect of sesame oil supplement on postmenopausal osteoporosis in rats. We used female Sprague Dawley rats that underwent bilaterally ovariectomy (OVX) as an experimental postmenopausal osteoporosis animal model. These rats were orally administrated sesame oil (0.25 or 0.5 mL/kg/day) for four months as the therapeutic group. We assessed bone mineral density (BMD) and the levels of osteocalcin, procollagen-I C-terminal propeptide (PICP), collagen cross-linked N-telopeptide (NTx), estradiol, and aromatase in the sera. The daily supplementation of sesame oil significantly increased BMD, serum osteocalcin levels, and trabecular areas in the OVX-treated rats. Sesame oil also elevated serum PICP levels and decreased NTx levels in these rats. Furthermore, sesame oil effectively maintained serum estradiol and aromatase levels in the OVX-induced osteoporosis rats. In conclusion, daily supplementation of sesame oil prevents postmenopausal osteoporosis by maintaining serum estrogen and aromatase levels, while also modulating the imbalance between bone formation and resorption in osteoporosis rats.

The Pulsed Nd:YAG Laser Therapy Enhanced Nerve Regeneration via Apoptosis Inhibition in a Rat Crushed Sciatic Nerve Model.

The study was aimed to validate the efficacy of the pulsed Nd:YAG laser on nerve regeneration in a rat sciatic nerve crushed model. 54 Wistar rats were randomly assigned into three groups: shame control, crush control, and laser treated group. For the laser treated group, the pulsed Nd:YAG laser (10 Hz) with 350 mJ per pulse in energy density and 50 J/cm2 in fluence was applied extracorporeally at the lesion site for 12 min to daily deliver 500 J immediately and consecutive 9 days following the crush injury. At week 1, the apoptosis-related activities in the injured nerve were examined (n = 8/each group). The sciatic functional index (SFI) was measured preoperatively and weekly until 4 weeks after the index procedure. The injured nerve and the innervated gastrocnemius muscle histology were assessed at week 4 (n = 10/each group). At week 1, the laser group showed the significant less TUNEL-positive ratio (P < 0.05), and the lower expression of cleaved caspase3/procaspase-3 and beclin-2/beclin-2-associated protein X ratios compared with the crush control. Furthermore, the laser group revealed significantly better SFI since week 1 and throughout the study (P < 0.05, all) compared with the crush control. At week 4, the laser group showed significantly higher axon density, lower myelin g-ratio, and the corresponding higher glycogen expression (P < 0.05, all) in the gastrocnemius muscle compared with those in the crush control. The pulsed Nd:YAG might enhance the injured nerve regeneration via apoptosis inhibition.

NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance.

Glucose metabolism is known to orchestrate oncogenesis. Whether glucose serves as a signaling molecule directly regulating oncoprotein activity for tumorigenesis remains elusive. Here, we report that glucose is a cofactor binding to methyltransferase NSUN2 at amino acid 1-28 to promote NSUN2 oligomerization and activation. NSUN2 activation maintains global m5C RNA methylation, including TREX2, and stabilizes TREX2 to restrict cytosolic dsDNA accumulation and cGAS/STING activation for promoting tumorigenesis and anti-PD-L1 immunotherapy resistance. An NSUN2 mutant defective in glucose binding or disrupting glucose/NSUN2 interaction abolishes NSUN2 activity and TREX2 induction leading to cGAS/STING activation for oncogenic suppression. Strikingly, genetic deletion of the glucose/NSUN2/TREX2 axis suppresses tumorigenesis and overcomes anti-PD-L1 immunotherapy resistance in those cold tumors through cGAS/STING activation to facilitate apoptosis and CD8+ T cell infiltration. Our study identifies NSUN2 as a direct glucose sensor whose activation by glucose drives tumorigenesis and immunotherapy resistance by maintaining TREX2 expression for cGAS/STING inactivation.

Survival benefit of sentinel lymph node biopsy in Asian melanoma patients.

Sentinel lymph node biopsy (SLNB) provides important prognostic information for early-stage melanomas. However, statistics regarding the survival comparison between SLNB and nodal observation in Asia, where acral lentiginous melanoma (ALM) predominates, are limited. This study aimed to identify if SLNB offered survival benefits over nodal observation in early-stage melanomas in Taiwan. The retrospective study included 227 patients who met the SLNB criteria according to the National Comprehensive Cancer Network guidelines and were treated at National Taiwan University Hospital from June 1997 to June 2021. Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards regression models. Of the study population, ALM accounted for 73.1%; 161 patients (70.9%) underwent SLNB and 66 patients (29.1%) were under nodal observation. Multivariate analysis showed significantly improved melanoma-specific survival (hazard ratio [HR], 0.6; p = .02) in the SLNB group. Among those who underwent completion lymph node dissection (CLND), the non-sentinel node positivity rate was 44.4%. Immediate CLND resulted in significantly longer melanoma-specific survival and distant-metastasis-free survival (DMFS) compared to nodal observation. (HR, 0.2; p = .01 for melanoma-specific survival. HR, 0.3; p = .046 for DMFS). In conclusion, SLNB may provide survival benefits of cutaneous melanoma over nodal observation in the Taiwanese population.

Full Endoscopic Spine Surgery for Cervical Spondylotic Myelopathy: A Systematic Review.

BACKGROUND: Cervical spondylotic myelopathy (CSM) may seriously affect quality of life. In the literature, there is scarce evidence of the pros and cons of full endoscopic spine surgery in the treatment of CSM. The main purpose of this study was to conduct a systematic review to elucidate the efficacy of full endoscopic spine surgery in the management of patients with CSM. METHODS: This systematic review was conducted in accordance with the PRISMA guidelines. A systematic search of Web of Science, PubMed MEDLINE, Embase, and Cochrane Library was conducted from the database inception to February 1, 2023. RESULTS: The study included 183 patients and their age was 56.78 ± 7.87 years. The average surgical time calculated was 96.34 ± 33.58 minutes. Intraoperative blood loss ranged from a minimal amount to 51 mL. The average duration of hospital stay was 3.56 ± 1.6 days. The average span for follow-up was on an interval of 18.7 ± 6.76 months. Significant improvements were noted in all aspects of functional outcomes and image results after full endoscopic cervical spine surgery, with no major complications. CONCLUSIONS: The current study found that both anterior transcorporeal and posterior surgical approaches could be used for the treatment of CSM with a full endoscopic technique. Indications of full endoscopic cervical spine surgery for CSM included cervical disc herniation, central canal stenosis, calcified ligamentum flavum, and ossification of the posterior longitudinal ligament. Improved postoperative outcomes with acceptable surgical complications were noted in this systematic review.

A Stabilized Kriging Method for Mapping Disease Rates.

BACKGROUND: Mapping disease rates is an important aspect of epidemiological research because it helps inform public health policy. Disease maps are often drawn according to local administrative areas (LAAs), such as counties, cities, or towns. In LAAs with small populations, disease rates are unstable and are prone to appear extremely high or low. The empirical Bayes methods consider variance differences among different LAAs, thereby stabilizing the disease rates. The methods of kriging break the constraints of geopolitical boundaries and produce a smooth curved surface in the form of contour lines, but the methods lack the stabilizing effect of the empirical Bayes methods. METHODS: An easy-to-implement stabilized kriging method is proposed to map disease rates, which allows different errors in different LAAs. RESULTS: Monte Carlo simulations revealed that the stabilized kriging method had smaller symmetric mean absolute percentage error than three other types of methods (the original LAA-based method, empirical Bayes methods, and traditional kriging methods) in nearly all scenarios considered. Real-world data analysis of oral cancer incidence rates in men from Taiwan demonstrated that the age-standardized rates in the central mountainous sparsely-populated region of Taiwan were stabilized using our proposed method, with no more large differences in numerical values, whereas the rates in other populous regions were not over-smoothed. Additionally, the stabilized kriging map had improved resolution and helped locate several hot and cold spots in the incidence rates of oral cancer. CONCLUSION: We recommend the use of the stabilized kriging method for mapping disease rates.

Triptolide Attenuates Muscular Inflammation and Oxidative Stress in a Delayed-Onset Muscle Soreness Animal Model.

Delayed-onset muscle soreness (DOMS) is associated with exercise-induced muscle damage and inflammation, which is mainly caused by prolonged eccentric exercise in humans. Triptolide, an extract from the Chinese herb Tripterygium wilfordii Hook F, has been used for treating autoimmune and inflammatory diseases in clinical practice. However, whether triptolide attenuates acute muscle damage is still unclear. Here, we examined the effect of triptolide on carrageenan-induced DOMS in rats. Rats were injected with 3% of carrageenan into their muscles to induce acute left gastrocnemius muscular damage, and triptolide treatment attenuated carrageenan-induced acute muscular damage without affecting hepatic function. Triptolide can significantly decrease lipid hydroperoxide and nitric oxide (NO) levels, proinflammatory cytokine production, and the activation of nuclear factor (NF)-ĸB, as well as increase a reduced form of glutathione levels in carrageenan-treated rat muscles. At the enzyme levels, triptolide reduced the inducible nitric oxide synthase (iNOS) expression and muscular myeloperoxidase (MPO) activity in carrageenan-treated DOMS rats. In conclusion, we show that triptolide can attenuate muscular damage by inhibiting muscular oxidative stress and inflammation in a carrageenan-induced rat DOMS model.

"Double Cross Sign" Could Be an Indicator of an Adequate Amount of Bone Cement in Kyphoplasty with the SpineJack System: A Retrospective Study.

Kyphoplasty with the SpineJack system was able to restore vertebral height and stabilize the vertebra with an injection of bone cement. The goal of this study was to seek a reliable assessing method during the surgery in determining the minimum amount of bone cement required for the SpineJack system to restore vertebral height and stabilize the vertebra. We defined the "double cross sign" as bone cement that expanded vertically along the bilateral SpineJack system, and spread across the midline of the vertebral body as viewed in the anteroposterior (AP) view of the radiographic image. Sixty-five patients aged 74.5 ± 8.5 years with vertebral compression fracture were included in the study. Patients with a positive double cross sign had better ODI score than those without the double cross sign (20.0 ± 6.9 vs. 32.3 ± 8.2; p < 0.001). Postoperative regional kyphotic and local kyphotic angle were significantly better in the positive double cross sign group (11 ± 8.8 degrees vs. 5.3 ± 3.2 degrees; p = 0.001/11.7 ± 6.2 degrees vs. 6.6 ± 4.1 degrees; p = 0.001, respectively). The more stable construct was built once the double cross sign was achieved during surgery. In this study, a convenient and intuitive method in identifying the minimum but sufficient quantity of injected cement during the SpineJack procedure was developed.

Deregulated transcription factors in cancer cell metabolisms and reprogramming.

Metabolic reprogramming is an important cancer hallmark that plays a key role in cancer malignancies and therapy resistance. Cancer cells reprogram the metabolic pathways to generate not only energy and building blocks but also produce numerous key signaling metabolites to impact signaling and epigenetic/transcriptional regulation for cancer cell proliferation and survival. A deeper understanding of the mechanisms by which metabolic reprogramming is regulated in cancer may provide potential new strategies for cancer targeting. Recent studies suggest that deregulated transcription factors have been observed in various human cancers and significantly impact metabolism and signaling in cancer. In this review, we highlight the key transcription factors that are involved in metabolic control, dissect the crosstalk between signaling and transcription factors in metabolic reprogramming, and offer therapeutic strategies targeting deregulated transcription factors for cancer treatment.

Cross-Linked Hyaluronate and Corticosteroid Combination Ameliorate the Rat Experimental Tendinopathy through Anti-Senescent and -Apoptotic Effects.

The combination of cross-linked hyaluronate (cHA) and corticosteroid showed more rapid pain or functional improvement in knee osteoarthritis and adhesive capsulitis. However, rare evidence of this combination in treating tendinopathy has been reported. We hypothesized that the specific formulations of cHA and dexamethasone (DEX) conferred amelioration of tendinopathy via anti-apoptosis and anti-senescence. In this controlled laboratory study, primary tenocytes from the human tendinopathic long head of biceps were treated with three cHA formulations (cHA:linealized HA = 80:20, 50:50, and 20:80) + DEX with or without IL-1ß stimulation. Cell viability, inflammatory cytokines, tendon-related proliferation markers, matrix metalloproteinases (MMPs), senescent markers, and apoptosis were examined. The in vivo therapeutic effects of the selected cHA + DEX combinations were evaluated in a collagenase-induced rat patellar tendinopathy model. The expression levels of inflammatory mediators, including IL-1ß, IL-6, COX-2, MMP-1, and MMP-3 were significantly reduced in all cHA + DEX-treated tenocytes (p < 0.05, all). The cHA (50:50) + DEX and cHA (20:80) + DEX combinations protected tenocytes from cytotoxicity, senescence, and apoptosis induced by DEX in either IL-1ß stimulation or none. Furthermore, the two combinations significantly improved the rat experimental tendinopathy by reducing ultrasound feature scores and histological scores as well as the levels of apoptosis, senescence, and senescence-associated secretory phenotypes (p < 0.05, all). We identified two specific cHA formulations (cHA (50:50) and cHA (20:80)) + DEX that could ameliorate tendinopathy through anti-senescence and -apoptosis without cytotoxicity. This study provides a possible approach to treating tendinopathy using the combination of two well-known agents.

Identification of myo-inositol-binding proteins by using the biotin pull-down strategy in cultured cells.

Metabolites are not only substrates in metabolic reactions, but they also serve as signaling molecules to regulate diverse biological functions. Identification of the binding proteins for the metabolites helps in the understanding of their functions beyond the classic metabolic pathways in which they are involved. We provide the protocol for synthesizing the biotin-labeled myo-inositol, which is used to identify its binding proteins by using biotin pull-down assay, given there is no available tool for the rapid screening of inositol-binding proteins in cells and in vitro systems. Biotin-labeled inositol probe therefore provides a tool to identify inositol's sensors. For complete details on the use and execution of this protocol, please refer to Hsu et al. (2021).

Risk factors for lymphatic and hematogenous metastasis after diagnosis of cutaneous Melanoma in Taiwan.

BACKGROUND: Risk factors of lymphatic and hematogenous metastasis in cutaneous melanoma remained unclear in Asian population. This study aimed to identify clinical and histopathological factors to predict metastatic pathways in cutaneous melanoma in Taiwan. METHODS: A total of 247 patients diagnosed as stage I and II melanoma, followed at National Taiwan University Hospital were included in this retrospective study from 1980 to 2020. Kaplan-Meier curves and Cox proportional hazards regression were utilized to identify risk factors. RESULTS: During a median follow-up of 143 months, 48 (19.4%) and 62 (25.1%) patients developed lymphatic and hematogenous metastasis respectively. In the univariate analysis, age> 70 years, greater Breslow thickness, ulceration, neurotropism, and NRAS mutation were significant risk factors for lymphatic metastasis in all subtypes of melanoma. Age >70 years, head and neck location, thickness, ulceration, higher mitotic rate, neurotropism, and NRAS mutation were significant predictors of hematogenous metastasis in all subtypes. In the multivariate analysis, greater thickness (HR for 2.0-4.0 mm, 4.5; p = .009 and HR for >4.0 mm, 5.7; p = .003) retained its significance as an independent risk factor for lymphatic metastasis in all subtypes of melanoma. Thickness (HR for >4.0 mm, 5.7; p < .001) and ulceration (HR, 2.5; p = .001) were independent risk factors for hematogenous metastasis. CONCLUSION: Risk factors of metastasis not only differ between lymphatic and hematogenous pathways, but also differ between ethnics and melanoma subtypes. Better understanding the behavior of cutaneous melanoma may help guide further treatments and follow-up plans.

SIRPγ-expressing cancer stem-like cells promote immune escape of lung cancer via Hippo signaling.

Cancer stem-like cells (CSLCs) acquire enhanced immune checkpoint responses to evade immune cell killing and promote tumor progression. Here we showed that signal regulatory protein γ (SIRPγ) determined CSLC properties and immune evasiveness in a small population of lung adenocarcinoma (LUAD) cancer cells. A SIRPγhi population displayed CSLC properties and transmitted the immune escape signal through sustaining CD47 expression in both SIRPγhi and SIRPγlo/- tumor cells. SIRPγ bridged MST1 and PP2A to facilitate MST1 dephosphorylation, resulting in Hippo/YAP activation and leading to cytokine release by CSLCs, which stimulated CD47 expression in LUAD cells and consequently inhibited tumor cell phagocytosis. SIRPγ promoted tumor growth and metastasis in vivo through YAP signaling. Notably, SIRPγ targeting with genetic SIRPγ knockdown or a SIRPγ-neutralizing antibody inhibited CSLC phenotypes and elicited phagocytosis that suppressed tumor growth in vivo. SIRPG was upregulated in human LUAD and its overexpression predicted poor survival outcome. Thus, SIRPγhi cells serve as CSLCs and tumor immune checkpoint-initiating cells, propagating the immune escape signal to the entire cancer cell population. Our study identifies Hippo/YAP signaling as the first mechanism by which SIRPγ is engaged and reveals that targeting SIRPγ represents an immune- and CSLC-targeting strategy for lung cancer therapy.

AMPK signaling and its targeting in cancer progression and treatment.

The intrinsic mechanisms sensing the imbalance of energy in cells are pivotal for cell survival under various environmental insults. AMP-activated protein kinase (AMPK) serves as a central guardian maintaining energy homeostasis by orchestrating diverse cellular processes, such as lipogenesis, glycolysis, TCA cycle, cell cycle progression and mitochondrial dynamics. Given that AMPK plays an essential role in the maintenance of energy balance and metabolism, managing AMPK activation is considered as a promising strategy for the treatment of metabolic disorders such as type 2 diabetes and obesity. Since AMPK has been attributed to aberrant activation of metabolic pathways, mitochondrial dynamics and functions, and epigenetic regulation, which are hallmarks of cancer, targeting AMPK may open up a new avenue for cancer therapies. Although AMPK is previously thought to be involved in tumor suppression, several recent studies have unraveled its tumor promoting activity. The double-edged sword characteristics for AMPK as a tumor suppressor or an oncogene are determined by distinct cellular contexts. In this review, we will summarize recent progress in dissecting the upstream regulators and downstream effectors for AMPK, discuss the distinct roles of AMPK in cancer regulation and finally offer potential strategies with AMPK targeting in cancer therapy.

Restoring Osteochondral Defects through the Differentiation Potential of Cartilage Stem/Progenitor Cells Cultivated on Porous Scaffolds.

Cartilage stem/progenitor cells (CSPCs) are cartilage-specific, multipotent progenitor cells residing in articular cartilage. In this study, we investigated the characteristics and potential of human CSPCs combined with poly(lactic-co-glycolic acid) (PLGA) scaffolds to induce osteochondral regeneration in rabbit knees. We isolated CSPCs from human adult articular cartilage undergoing total knee replacement (TKR) surgery. We characterized CSPCs and compared them with infrapatellar fat pad-derived stem cells (IFPs) in a colony formation assay and by multilineage differentiation analysis in vitro. We further evaluated the osteochondral regeneration of the CSPC-loaded PLGA scaffold during osteochondral defect repair in rabbits. The characteristics of CSPCs were similar to those of mesenchymal stem cells (MSCs) and exhibited chondrogenic and osteogenic phenotypes without chemical induction. For in vivo analysis, CSPC-loaded PLGA scaffolds produced a hyaline-like cartilaginous tissue, which showed good integration with the host tissue and subchondral bone. Furthermore, CSPCs migrated in response to injury to promote subchondral bone regeneration. Overall, we demonstrated that CSPCs can promote osteochondral regeneration. A monophasic approach of using diseased CSPCs combined with a PLGA scaffold may be beneficial for repairing complex tissues, such as osteochondral tissue.

NOX2-Deficient Neutrophils Facilitate Joint Inflammation Through Higher Pro-Inflammatory and Weakened Immune Checkpoint Activities.

Immune-mediated arthritis is an important chronic inflammatory disease of joints causing debilitating morbidity in affected patients. The mechanisms underlying immune-mediated arthritis have been intensively investigated, however the cellular and molecular factors contributing to the joint inflammation in different redox conditions have not been clearly elucidated. Previous research showed that phagocyte-produced reactive oxygen species (ROS) plays an anti-inflammatory role in K/BxN serum-transfer arthritis and NOX2-deficient mice tend to have more severe arthritis. Although many leukocytes play critical roles in the development of immune-mediated arthritis, the role of neutrophils, which are the main producers of ROS in inflammation, is still controversial. We hence assessed the immunomodulatory function of neutrophils from arthritic joints of NOX2-deficient and wild type mice in this study. We found more neutrophils accumulation in NOX2-deficient inflamed joints. RNA-sequencing and quantitative PCR revealed significantly increased expression of acute inflammation genes including IL1b, Cxcl2, Cxcl3, Cxcl10 and Mmp3 in activated neutrophils from the inflamed joints of NOX2-deficient mice. Moreover, gene set enrichment analysis (GSEA) showed enriched gene signatures in type I and II IFN responses, IL-6-JAK-STAT3 signaling pathway and TNF-α signaling pathway via NF-κB in NOX2-deficient neutrophils. In addition, we found that NOX2-deficient neutrophils expressed lower levels of PD-L1 and were less suppressive than WT neutrophils. Moreover, treatment of PD-L1-Fc decreased cytokine expression and ameliorated the severity of inflammatory arthritis. Our results suggest that NOX2-derived ROS is critical for regulating the function and gene expression in arthritic neutrophils. Both the strong pro-inflammatory and weakened anti-inflammatory functions of neutrophils due to abnormal redox regulation may be targets of treatment for immune-mediated arthritis.

Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK.

Mitochondrial dynamics regulated by mitochondrial fusion and fission maintain mitochondrial functions, whose alterations underline various human diseases. Here, we show that inositol is a critical metabolite directly restricting AMPK-dependent mitochondrial fission independently of its classical mode as a precursor for phosphoinositide generation. Inositol decline by IMPA1/2 deficiency elicits AMPK activation and mitochondrial fission without affecting ATP level, whereas inositol accumulation prevents AMPK-dependent mitochondrial fission. Metabolic stress or mitochondrial damage causes inositol decline in cells and mice to elicit AMPK-dependent mitochondrial fission. Inositol directly binds to AMPKγ and competes with AMP for AMPKγ binding, leading to restriction of AMPK activation and mitochondrial fission. Our study suggests that the AMP/inositol ratio is a critical determinant for AMPK activation and establishes a model in which AMPK activation requires inositol decline to release AMPKγ for AMP binding. Hence, AMPK is an inositol sensor, whose inactivation by inositol serves as a mechanism to restrict mitochondrial fission.

Author Correction: SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis.

A Correction to this paper has been published: https://doi.org/10.1038/s41556-021-00686-x.